Metal-Free Reduction of Aromatic Nitro Compounds to Aromatic Amines with B2pin2 in Isopropanol

Article abstract of DOI:10.1021/acs.orglett.6b01274

A metal-free reduction of aromatic nitro compounds to the corresponding amines has been achieved by a combination of B₂pin₂ and KOtBu in isopropanol. A series of nitro compounds containing various reducible functional groups were chemoselectively reduced in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b01274

Letter
pubs.acs.org/OrgLett
Metal-Free Reduction of Aromatic Nitro Compounds to Aromatic
Amines with B pin in Isopropanol
2
2
Hongtao Lu, Zhiyue Geng, Jingya Li, Dapeng Zou,* Yusheng Wu,* and Yangjie Wu*,†
†
†
‡
,†
,‡,§
†
The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, People’s Republic of China
‡
Tetranov Biopharm, LLC. and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052,
People’s Republic of China
§
Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New Brunswick, New Jersey 08901, United States
*
S Supporting Information
ABSTRACT: A metal-free reduction of aromatic nitro
compounds to the corresponding amines has been achieved
by a combination of B pin and KOtBu in isopropanol. A
2
2
series of nitro compounds containing various reducible
functional groups were chemoselectively reduced in good to excellent yields.
eduction of functionalized aromatic nitro compounds to
aromatic amines is a valuable reaction due to the fact that
there are still some drawbacks: the lack of chemoselectivity, the
R
use of special high pressure equipment, inflammable hydrogen
gas, hazardous reagents, relatively expensive metal complexes,
and long reaction times. Given these facts, it is still very desirable
to develop new, economical, and efficient methods for the highly
chemoselective reduction of aromatic nitro compounds,
especially under mild and user-friendly conditions.
the products are widely used as central intermediates and key
precursors in the synthesis of many pharmaceuticals, dyes,
1
agrochemicals, and polymers. Plentiful strategies have been
developed to complete this transformation. In general, this
transformation has been accomplished mainly by two methods.
1) Metal-based methods: the reactions using a large excess of
(
Bis(pinacolato)diboron (B pin ) is widely used as a stable,
2
2
Zn, Fe, or SnCl in the presence of an acid are usually considered
13
2
green, and cheap reagent in borylation reactions. The
combination of B pin and a Lewis base, in particular, has been
2
to be the classical reduction methods. The metal catalytic
2
2
hydrogenation in the presence of H or stoichiometric amounts
2
recognized as an efficient reagent for the metal-free borylation of
of other reducing agents can also reduce nitro groups (Scheme
a). Recently, Beller and co-workers developed some excellent
14
some special molecules. However, the direct use of these
3
1
reagents for reduction has been rarely studied. Recently, Mahesh
K. Lakshman and Jacques Einhorn et al. disclosed the facile
reduction of amine N-oxides and cleavage reaction of the N−O−
Scheme 1. Different Methods for the Reduction of Aromatic
Nitro Compounds
15
H bonds based on the use of B pin , independently. To the best
2
2
of our knowledge, no synthetic route to aromatic amines by
reduction of aromatic nitro compounds with B pin has been
2
2
reported. Herein, we report a novel protocol for the chemo-
selective reduction of aromatic nitro compounds to the
corresponding amines using B pin activated by KOtBu in
2
2
isopropanol (Scheme 1c).
Our initial studies were carried out by examining 1-bromo-4-
nitrobenzene (1a, 1.0 equiv) and B pin (2, 3.0 equiv) in the
2
2
presence of Cs CO in MeOH at 80 °C for 8 h (Table 1, entry 1).
2
3
The desired product 3a was observed in 85% yield in LC-MS
without byproducts. Encouraged by this preliminary result,
various bases were studied, and an excellent yield of 3a was
afforded when KOtBu was employed (entry 5). In addition,
almost no reaction occurred in the presence of other weaker
bases (entries 2, 3) or some organic bases (see Supporting
Information). Notably, the reaction did not work without a base
(entry 8), so the base is essential for this reaction.
Co O4 and Fe O based heterogeneous catalysts for the
3
2
3
4
hydrogenation of nitroarenes. (2) Metal-free methods: these
available methods incorporate the use of 9,10-dihydroanthra-
5
6
7
cene, 1,4-dihydropyridines, thiols, (2-pyridyl)phenyl-
8
9
methanol, fullerenes/H , reduced grapheme oxide/hydrazine-
hydrate, and vasicine. Moreover, Benaglia et al. reported the
chemoselective reduction of aromatic and aliphatic nitro
2
1
0
11
12
compounds to amines by using HSiCl with TEA (Scheme
Received: May 2, 2016
3
1b). Although several of these protocols have been used widely,
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01274
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Reduction of Various Nitro Compounds with
a b
,
B2pin2
b
entry
base (equiv)
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
Cs CO (2.0)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
50
rt
8
85
2
3
Na CO (2.0)
8
trace
trace
80
2
3
K CO (2.0)
8
2
3
NaOMe (2.0)
KOtBu (2.0)
NaOtBu (2.0)
LiOtBu (2.0)
−
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (1.2)
KOtBu (0.5)
KOtBu (1.2)
KOtBu (1.2)
KOtBu (1.2)
8
8
89
8
75
8
74
8
n.r.
89
8
10
11
12
13
14
15
16
17
18
19
20
iPrOH
tBuOH
dioxane
THF
8
91
8
84
8
12
8
9
toluene
8
13
H O
2
8
trace
88
c
c
c
c
c
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
8
12
24
24
2
70
65
trace
96/87
d
110
a
Reaction conditions: 1a (1.0 mmol), 2 (3.0 mmol), base (2.0 mmol),
.0 mL of solvent, 80 °C. HPLC yield. 3.1 equiv of 2. Isolated yield.
b
c
d
4
n.r. = no reaction.
a
Standard reaction conditions: 1 (1.0 mmol), 2 (3.1 mmol), KOtBu
(
1.2 mmol) in 4 mL of iPrOH at 110 °C for 2 h (as to the heterocyclic
Through the screening of solvents, protic solvents were found
b
nitro compounds, the reaction time is 0.5 h). Determined by LC-MS
analysis of the crude reaction mixture, with the isolated yield in
parentheses. Isolated as 4-acetylamino benzoic acid. Isolated as a
to achieve higher yields in the reaction except for H O (entry
2
1
5). By contrast aprotic solvents were less effective (entries 9−11
c
d
vs 12−14). iPrOH was found to be the best solvent (91%, entry
mixture of 3n and isopropyl 4-aminobenzoate.
1
6
1
0). Furthermore, we found that the yield of the product was
not affected when the amount of KOtBu decreased to 1.2 equiv
88% yield, entry 16). When the amount of KOtBu was
(
hydroxyl group (3j). 4-Nitrophenol containing protecting
groups such as benzyl and benzoyl can be reduced in moderate
to good yields (3k and 3l). 4-Nitrobenzoic acid was reduced in
high yield (89%) by increasing the amount of KOtBu to 2.5
equiv. The excess base was used for neutralizing the acidity of the
substrate initially, and the product was isolated as 4-acetylamino
benzoic acid for easy purification (3m). Ester groups also
tolerated the reaction conditions, and a mixture of 3n and
isopropyl 4-aminobenzoate was obtained, because of the
transesterification of methyl 4-nitrobenzoate. Nitrobenzene
with an amide functional group was also smoothly reduced in
high yield (3o). It is noteworthy that some reducible functional
groups such as cyano and alkynyl are minimally affected under
our conditions (3p, 3q). However, because of the reduction of
the aldehyde group, 4-nitrobenzaldehyde gives the desired
aniline in trace yield with a complex mixture even in low
temperature under these conditions (3r). Nitrobenzene can be
reduced by extending the time, and a moderate yield was
observed (3s). This transformation can also be successfully
extended to heterocyclic nitro compounds to form the
corresponding heterocyclic aromatic amines in 73−90% yields
within 30 min (3t−3y).
decreased to the catalyst loading amount (entry 17), the starting
material 1a was not completely consumed. By increasing the
amount of B pin to 3.1 equiv the conversion of the starting
2
2
material increased (see Supporting Information). The reaction
temperature was also screened. Lowering the reaction temper-
ature did not favor the reaction, even when prolonging the
reaction time to 24 h (entries 18, 19). High temperature can
promote this transformation, and 96% of desired product was
achieved at 110 °C in 2 h (entry 20). Additionally, some other
boron sources were investigated (see Supporting Information)
and the results indicated that diboron reagents are the most
suitable ones to accomplish this reaction in good yields. Finally,
the optimized reaction conditions for the reduction of aromatic
nitro compounds (1.0 equiv) to the corresponding aromatic
amines were determined as the combination of B pin (3.1
2
2
equiv) with KOtBu (1.2 equiv) in iPrOH at 110 °C for 2 h.
With the optimal reaction conditions in hand, the scope of the
reduction of aromatic nitro compounds was explored (Scheme
2). The nitro group is chemoselectively reduced in the presence
of all halogen groups in our protocol, which afford the desired
halogenated anilines in good to excellent yields (60%−91%), and
without any dehalogenation in these cases (3a−3i). The
reactivity of 4-nitrophenol was not effective, even when
increasing the equivalents of KOtBu and extending the reaction
time, which could be attributed to the acidity of the phenolic
To gain insight into the reaction mechanism, a series of control
experiments and 11B NMR experiments were performed (see
Supporting Information). When B pin or KOtBu was used
2
2
alone, there is no reaction under optimal conditions. A major
B
DOI: 10.1021/acs.orglett.6b01274
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
1
peak at 22.3 ppm was observed in the B NMR spectrum of the
reaction mixture, which was consistent with 2-isopropoxy-
4
ACKNOWLEDGMENTS
We are grateful to Technology Research and Development
Funds of Zhengzhou (141PRCYY516) for financial support.
■
,4,5,5-tetramethyl-1,3,2-dioxaborolane (iPrOBpin), and this
byproduct was also detected by GC-MS. More than 3.0 equiv
of B pin are needed in this reaction. Based on the results
mentioned above and the literature reports, a putative reaction
pathway is shown in Scheme 3. Initially, isopropanol is
2
2
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2
2
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(
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17
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4
́
́
́
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01274.
(b) Kokatla, H. P.; Thomson, P. F.; Bae, S.; Doddi, V. R.; Lakshman, M.
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AUTHOR INFORMATION
Corresponding Authors
■
*
*
*
deoxygenation of B pin and transfer hydrogenation are involved, see:
refs 15a, 15b, and: Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621.
2
2
E-mail: zdp@zzu.edu.cn.
E-mail: yusheng.wu@tetranovglobal.com.
E-mail: wyj@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01274
Org. Lett. XXXX, XXX, XXX−XXX